The Neurophysiology of Pain During REM Sleep

In the last post, we learned about The Phenomenology of Pain During REM Sleep. Real life pain can intrude into dreams, as was shown for experimentally induced pain (Nielsen et al., 1993) and in hospitalized burn patients (Raymond et al., 2002). In this post we'll hear about a fascinating experiment that recorded laser evoked potentials directly from the brains of epilepsy patients who were being surgically monitored for seizures (Bastuji et al. 2011). Only under rare circumstances can intracranial electrodes be placed in the brains of humans, and the current study had the unique opportunity to record from three major pain regions simultaneously: the posterior insula (Brodmann area 13), the parietal operculum (somatosensory area S2), and the mid-anterior cingulate cortex (BA 24). These areas comprise the so-called "Pain Matrix"¹ (PM), or

network of cortical structures that respond consistently to noxious mechanical or thermal stimuli. The lateral structures of the PM (posterior insula and suprasylvian operculum) are thought to subserve intensity coding and localization of pain inputs, while the medial PM system (anterior and mid-cingulate cortex) is linked to the attentional (orienting and arousing) components of pain.

In the present study, Bastuji et al. (2011) recorded laser evoked potentials (LEPs) from these brain regions during different stages of sleep, as well as while the patients were awake. LEPs are a specific type of EEG response time-locked to the application of painful laser heat stimuli. When recorded from the scalp, a sequence of three LEPs is generated in rapid succession, within the first 400 milliseconds after laser stimulation. As described in a review by Plaghki and Mouraux (2005),

Laser heat stimulators selectively activate Aδ and C-nociceptors ["pain receptors"] in the superficial layers of the skin. Their high power output produces steep heating ramps, which improve synchronization of afferent volleys and therefore allow the recording of time-locked events, such as laser-evoked brain potentials. Study of the electrical brain activity evoked by Aδ- and C-nociceptor afferent volleys revealed the existence of an extensive, sequentially activated, cortical network.

The advantage of recording intracranial LEPs is that you know precisely when the pain-related activity occurred, as well as where the brain response was located (unlike with standard EEG). Two major components were observed: Component 1 (C1), peaking at ~200 ms post-stimulus and Component 2 (C2), peaking at ~300 ms. Because the components were of varying polarities depending on brain region, they weren't labelled according to the customary N2/P2 as seen on the scalp. Of primary interest was what happened to these components during Stage 2 sleep and REM sleep (see Fig. 3A below).


Figure 3A (modified from Bastuji et al. 2011). Grand average LEPs in referential recording mode during wakefulness, sleep stage 2, and paradoxical sleep in the operculum (bottom), the insula (middle), and the mid-anterior cingulate (top). Traces recorded by the electrode contact yielding the largest amplitudes are superimposed on those from the adjacent contact. On the left part of the figure, for each structure, the coordinates of the contacts where the maximal amplitudes of the C1–C2 components were recorded are indicated on mean sagittal MRIs.


Typically, painful stimuli at the nociceptive threshold will cause awakening ~30% of the time. In this study, the stimulus intensity of the laser² was set individually in each participant to be slightly above pain threshold. C1 and C2 decreased in amplitude in all three brain regions during Stage 2 sleep, relative to wakefulness. During REM sleep, however, both components remained stable in amplitude (relative to Stage 2) in the operculum and insula, but they decreased dramatically in the cingulate. Recall that the medial mid-anterior cingulate cortex (ACC) is associated with the attentional and affective components of pain, while the lateral opercular and insular cortices are more related to the sensory aspects of pain. The authors suggest that this dissociation between the lateral and medial pain systems is what allows the experience of pain in dreams without being alerted enough to wake up. The fact that larger mid-ACC LEPs can predict when motor responses to pain will occur supports this interpretation.


CODA (Notes from an Actual Pain Dream)

Lately I've had a painful orthopedic issue (in real life). I also have a cat who is fond of laying on my legs at night, which is not comfortable at all under the circumstances. Yesterday morning, I had a terrible nightmare in which my real life leg pain was projected onto someone else in an exceptionally gruesome way. I was driving along an unknown neighborhood street when suddenly a man appeared in front of my car. It wasn't clear if he was on the hood or on the trunk of the car ahead of me or suspended in the air in a dream-like way. At any rate, if that wasn't bad enough, he pulled up the body of a man who had fallen under my car and had both his legs amputated from being run over -- one leg was amputated below the knee, the other was at the hip. The gravely injured man was still alive. I was absolutely horrified. All I could do is say "oh my god oh my god oh my god" over and over. At some point my car rolled backward down a steep hill and the other motorists behind me were exclaiming "oh my god oh my god" as well.

It was an awful nightmare, and in the dream I was quite traumatized by the entire experience. Did I feel excruciating pain when I woke up? No, not really, just the usual ache.


Further Reading

LEPs and pain perception can be reduced while looking at one's own hand or at beautiful artwork:

It Hurts Less When I Can See It

Pain & Paintings: Beholding Beauty Reduces Pain Perception and Laser Evoked Potentials

Footnotes

¹ "So-called" because the Pain Matrix might not be that specific to nociception after all (Iannetti & Mouraux, 2010).

² Laser pulses were delivered to the back of the hand opposite to the hemisphere with the implanted electrodes.

References

Bastuji, H., Mazza, S., Perchet, C., Frot, M., Mauguière, F., Magnin, M., & Garcia-Larrea, L. (2011). Filtering the reality: Functional dissociation of lateral and medial pain systems during sleep in humans. Human Brain Mapping DOI: 10.1002/hbm.21390

Iannetti GD, Mouraux A. (2010). From the neuromatrix to the pain matrix (and back). Exp Brain Res. 205:1-12.

Nielsen TA, McGregor DL, Zadra A, Ilnicki D, & Ouellet L (1993). Pain in dreams. Sleep 16:490-8.

Plaghki L, Mouraux A. (2005). EEG and laser stimulation as tools for pain research. Curr Opin Investig Drugs 6:58-64. PDF

Raymond I, Nielsen TA, Lavigne G, Choinière M. (2002). Incorporation of pain in dreams of hospitalized burn victims. Sleep 25:765-70.

The Phenomenology of Pain During REM Sleep

Coarse — Pain in Dreams

Have you ever felt pain in dreams? I have. Once I dreamed I was lying on my stomach, getting a tattoo on my calf against my will. Because it was a particularly malevolent tattoo studio, I cried out in the dream. When I woke up, I felt no pain at all. It was false, a figment of the Pain Matrix. Another time a monkey bit me on the arm. Once again, the pain vanished upon awakening.

I think these examples of what I'll call "fake pain" are unusual. More common are instances when you get a calf cramp or have pins and needles in your arm while sleeping, and this real life pain gets incorporated into dreams about tattoos or monkey bites. But even these possibilities have been discounted as unlikely, because of limitations on which sensory modalities can be represented in dreams (Nielsen et al., 1993):

One possibility is that pain is beyond the representational capability of image formation processes -- that neither pain memories nor pain images are reproducible in the dreaming mode. A second possibility is that the sensory systems that might contribute to the representation of pain imagery are not functional during dreaming. This possibility is consistent with the finding that the high threshold polysynaptic afferent fibers that conduct pain sensations are actively inhibited during REM sleep in cats.

But plenty of people have reported feeling pain in dreams, so why construct hypotheses about why it's impossible? So skeptics Tore A. Nielsen and three fellow psychology graduate students, along with an undergrad art therapy student, conducted experiments on themselves in a 1993 paper. They inflated a blood pressure cuff above the knee of their colleagues 5 min into a bout of REM sleep¹ [to produce ischemia of the leg muscles, i.e. pins and needles or paralysis].

Results indicated that pain sensations occurred in 13 out of 42 stimulation trials with usable dream reports (31%). In contrast, only one of the 21 non-stimulated control dreams contained a reference to pain (4.8%). Many of the dreams were realistic and took place in a sleep lab-like setting. Others were more fantastic; one was set at a rodeo, another at a dance party in a barn [the authors lived in Montreal]. Some were lucid², like the "ugly shoe" dream:

I'm in a small store trying on a pair of ugly shoes. I started walking. Then I staggered forward because I was waking up and not fully conscious. You were laughing at me. I said "come on, its not funny, I'm trying to wake up!" This is the second or third time I've been trying to wake up.

Some of the participants were more likely to experience pain dreams than others. Subject B, who reported pain dreams on 70% of the stimulation trials, had knee surgery a few years prior and still felt numbness or tingling sensations on occasion. Most of the time, the pain sensations occurred in the appropriate leg for all participants. Interestingly, the "crampy pressure", "tingling", or "hurting a bit" sensations felt upon awakening were much less intense than those that occurred during the dream.

When interpreting these subjective reports, one has to consider an expectation or priming effect, since all the students were focused on dream research, with extensive experience in the sleep lab. However, this was not the case in a study of 28 hospitalized burn patients (Raymond et al., 2002). Obviously, the severity of suffering in burn patients is intense and chronic, unlike having temporary "pins and needles" in your leg. Over a period of 5 days, pain dreams comprised 30% of all reported dreams, which is quite comparable to the artificial BP cuff study. The patients who reported pain dreams (39%) had more nightmares, worse sleep quality, and more post-traumatic stress symptoms. The other 61% of the patients did not have any pain dreams. Why?

What sort of neurophysiological activity can account for painful sensations that are experienced during REM sleep? We'll find out in the next post.


Footnotes

¹ It wasn't clear how they monitored for REM, since EEG methods were not described. However, the transcript of one dream suggested that EEG was in fact recorded:

Then I was trying to get comfortable on the bed. All the electrodes but one for the EEG had fallen off; the others were dangling free.

The dream transcript continues:

You said that this was too bad. I had tossed around in bed trying to get comfortable. It was really cold and hurt my backside. There was almost no mattress; I was on a board. I was saying to you that we had hit rock bottom in this bed.

The interesting part about this segment is that there was no BP cuff applied; out of 14 dreams this was the only one without external stimulation (kind of like my "fake pain" dreams).

² The subject was aware they were dreaming and tried to control the action.


References

Nielsen TA, McGregor DL, Zadra A, Ilnicki D, & Ouellet L (1993). Pain in dreams. Sleep, 16 (5), 490-8 PMID: 7690981

Raymond I, Nielsen TA, Lavigne G, Choinière M. (2002). Incorporation of pain in dreams of hospitalized burn victims. Sleep 25:765-70.

Was the "psychosis prevention" drug trial actually approved before it was terminated?

THIS POST WILL BE UPDATED AT A LATER TIME, PENDING OFFICIAL CLARIFICATION ABOUT THE APPROVAL AND TERMINATION OF THE TRIAL.

SORRY FOR THE INCONVENIENCE.

Chronic Ketamine for Depression: An Unethical Case Study?

A year ago, Ketamine for Depression: Yay or Neigh? covered acute administration of the club drug (and dissociative anesthetic) ketamine for rapid (albeit transient) relief of major depression. That post was part of a blog focus on hallucinogenic drugs in medicine and mental health, organized by Nature editor Noah Gray following publication of a review article on The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. At the time, I wrote:

Although the immediate onset of symptom amelioration gives ketamine a substantial advantage over traditional antidepressants (which take 4-6 weeks to work), there are definite limitations (Tsai, 2007). Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.

At present, what are the most promising uses for ketamine as a fast-acting antidepressant? Given the disadvantages discussed above, short-term use for immediate relief of life-threatening or end-of-life depressive symptoms seem to be the best indications.

For the past few weeks, I've been wanting to do a follow-up post that looks at the ups and downs of the mTOR (mammalian target of rapamycin) protein kinase pathway, which is rapidly activated by ketamine. Although activation of mTOR leads to the beneficial effect of increased synaptogenesis in the medial prefrontal cortex (Li et al., 2010), it can also cause accelerated tumor growth, as recently noted by Yang et al., 2011 ("Be prudent of ketamine in treating resistant depression in patients with cancer"). However, I've been unable to complete this planned post, specifically because the topic of ketamine use in palliative care settings is something I wrote about last year, while watching my father die of cancer.

More recently, an open label study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality.

To be blunt, the possibility of accelerated tumor growth is not an issue in terminal patients.

In terms of medical ethics, it's easier for me to take a different angle and address the unusual case of a grievously and chronically depressed patient (Messer & Haller, 2010). An anonymous reader alerted me to this paper, which isn't indexed in PubMed. The case history is as follows:

In January 2008, a 46-year old female with MDD was hospitalized for a course of electroconvulsive therapy (ECT). Successive interventions over 15 years had included trials of 24 psychotropic medications and 273 ECT treatments, 251 of which were bilateral [which can produce significant amnesia]. No intervention had produced remission but only a short-lived response to treatment...

ECT during this admission was administered with ketamine as the anesthetic at 2 mg/kg given over 60 seconds. Surgical anesthesia occurred ~30 seconds after the end of intravenous injection and lasted ~10 minutes. There was no significant change in depression symptoms with the ketamine used as an anesthetic during the ECT treatment. Alternative treatments were reviewed for potential use. In addition to no significant recovery from her depression, the long-term use of ECT caused problems with memory loss and focused attention. She was unable to remember much of her history over the previous 15 years. Re-learning the information became futile since each course of ECT would eliminate what had been gained.

I'm not going to weigh in here on ECT, beyond saying that it can be beneficial in some intractable patients [with fewer amnestic effects if unilateral]. But here we have an individual with profound ECT-induced amnesia who, although giving informed consent, was then treated with a highly unorthodox regimen of repeated ketamine infusions. The majority of registered clinical trials administer a single dose of ketamine, with one trial administering 5 additional ketamine infusions over a 2-week period. Relapse typically occurs within a week after a single dose.

On the other hand Dr. Messer's clinical trial, Ketamine Frequency Treatment for Major Depressive Disorder, was withdrawn prior to enrollment because pilot study determined the trial would not be feasible. The planned regimen was 6 injections every other day for 12 days. But the actual treatment given to the 46 yr old woman was much more extensive: 22 doses over 4 months, followed by 21 doses over 1 yr (approximately):

The first ketamine treatment led to a dramatic remission of depressive symptoms: the Beck Depression Inventory (BDI) score decreased from 22 to 6 (Figure). Three additional infusions administered every other day over 5 days produced remission lasting 17 days after the last infusion in this series. Three series of six ketamine infusions given every other day except weekends were repeated over the next 16 weeks (Figure). Each infusion sequence produced remission lasting 16, 28, and 16 days, respectively, followed by a relapse. After three remission/relapse cycles and before relapse could occur after the fourth infusion series, a maintenance ketamine regimen was established on August 27, 2008 using 0.5 mg/kg IBW at a 3-week inter-dose interval. The authors’ estimation for the maintenance dosing interval was based on the time frame between remission and relapse for this patient. Relapse to depression was prevented by treating prior to the onset of a relapse.

First, I was struck by the starting BDI score of 22, which falls within the low end of moderate depression, with scores of 29-63 indicating severe depression. I don't want to question Dr. Messer's clinical diagnosis of the patient, but I would guess that a typical BDI II score of 22 might not call for drastic measures. But perhaps the original BDI was used, in which case 19-29 indicates moderate-severe depression (which is still not severe). Second, the number of infusions went well beyond what has been established as safe, particularly in the context of treatment-resistant depression.

- click on image for a larger view -

What were the cognitive effects? We don't really know, because there was no formal testing:

As shown in the Figure, with maintenance infusions the patient has been in remission for >15 months. No concurrent pharmacotherapeutic agents have been administered or required during this time period, no adverse events have emerged, and there has been no cognitive impairment as is typical with ECT, polypharmacy, or from MDD itself.

What we do know is that ketamine is cost-effective relative to ECT:

The cost and personnel needed for a ketamine treatment are far less than that of ECT since no charges associated with anesthesia or operating room use are needed. The data from our institution suggest that the charges associated with one ketamine treatment are ~33% of the charges for one ECT.

But it's caution, and not cost-effectiveness, that should be of the utmost importance in vulnerable, chronically depressed patients who are treatment-resistant.


References

aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67:139-45.

Irwin SA, Iglewicz A. (2010). Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 13:903-8.

Javitt DC. (2010). Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 47:4-16.

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959-64.

Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, Liu T, Chen X, Fletcher PC, Hao W. (2010). Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain 133:2115-22.

Messer M, Haller IV (2010). Maintenance Ketamine Treatment Produces Long-term Recovery from Depression. Primary Psychiatry, 17, 48-50.

Tsai GE. (2007). Searching for rational anti N-methyl-D-aspartate treatment for depression. Arch Gen Psychiatry 64:1099-100; author reply 1100-1.

Vollenweider F, Kometer M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders Nature Reviews Neuroscience, 11 (9), 642-651.

Yang C, Zhou ZQ, Yang JJ. (2011). Be prudent of ketamine in treating resistant depression in patients with cancer. J Palliat Med. 14:537.

Dedication:

For my father, who has been deeply missed since September 6, 2010.

Drug Trials in 'At Risk' Youth

Is it ethical to medicate healthy teenagers "at risk" of developing psychosis to prevent a symptom that may not occur? One such clinical trial in Australia was recently stopped before it could even begin:

Drug trial scrapped amid outcry

Jill Stark

August 21, 2011



FORMER Australian of the Year Patrick McGorry has aborted a controversial trial of antipsychotic drugs on children as young as 15 who are "at risk" of psychosis, amid complaints the study was unethical.

The Sunday Age can reveal 13 local and international experts lodged a formal complaint calling for the trial not to go ahead due to concerns children who had not yet been diagnosed with a psychotic illness would be unnecessarily given drugs with potentially dangerous side effects.

Quetiapine, sold as Seroquel, has been linked to weight gain and its manufacturer AstraZeneca, which was to fund the trial, last month paid $US647 million ($A623 million) to settle a lawsuit in the US, alleging there was insufficient warning the drug may cause diabetes.

Dr. McGorry works at Orygen Youth Health in Parkville (near Melbourne) and is a proponent of early interventions for treating mental illness and substance abuse (McGorry et al., 2011). In discussing psychotic disorders, these authors say:

The importance of timely treatment initiation has been further underscored by new data from the Treatment and Intervention in Psychosis (TIPS) project showing that early treatment had positive effects on clinical and functional status at 2-year and 5-year follow-up in first episode psychosis. These studies showed that reducing the duration of untreated psychosis has longer-term effects on the course of negative symptoms, depressive symptoms, cognitive symptoms and social functioning, suggesting the possibility of secondary prevention of these pathologies in first-episode schizophrenia.

But how about prevention, as opposed to early intervention? Are researchers and clinicians able to predict (with reasonable accuracy) who will develop schizophrenia? The scrapped clinical trial intended to see whether quetiapine would decrease or delay the risk to 15-40 yr old participants who showed "early signs" of developing a psychotic disorder. What are these early signs and prodromal symptoms (Mechelli et al., 2011)?

...a gradual deterioration of global and social functioning and the emergence of attenuated psychotic symptoms. However, not all people with these features progress to develop a full-blown psychotic disorder; 20% to 50% develop psychosis, usually within 24 months, but the remainder do not. Individuals first seen with this clinical syndrome are, thus, said to be at ultra-high risk (UHR) for psychosis.

So anywhere from 50% to 80% of those showing prodromal symptoms and labeled ultra-high risk do not develop a psychotic disorder such as schizophrenia. Can neuroimaging improve this crude level of prediction? Ultimately, disordered thinking, delusions, and hallucinations arise from the brain -- right? -- so we should be able to see some abnormality on an MRI scan. A multi-site study enrolled 182 individuals at UHR for psychosis and 167 healthy controls. Voxel-based morphometry was used to quantify whole brain gray matter volumes, as well as 3 specific regions of interest (ROIs): the left parahippocampal gyrus in the medial temporal lobe (important for memory), the right inferior frontal gyrus (important for attention and cognitive control), and the left superior temporal gyrus (which may be implicated in auditory verbal hallucinations). Two years later, 48 UHR participants (26%) developed psychosis and the others did not.



Compared to controls, all subjects in the UHR group showed gray matter reductions in medial frontal regions, so this result was not predictive of whether full-blown psychosis would occur. Within the UHR group, however, a tiny region in the left anterior parahippocampal gyrus (6 voxels) differed in the UHR who later developed psychosis and those who did not. There were no volume reductions in the other two ROIs.

Figure 2 (adapted from Mechelli et al., 2011). Differences between ultra-high-risk (UHR) individuals who did (UHR-T) and did not (UHR-NT) develop psychosis. The UHR-T individuals had less gray matter volume than did the UHR-NT individuals in the left parahippocampal gyrus, bordering the uncus (MNI [Montreal Neurological Institute] coordinates x, y, and z: –21, 6, and –27, respectively). For visualization purposes, effects are displayed at P < .05 uncorrected.



So basically, only 6 voxels in the entire brain were capable of predicting whether or not a patient at ultra-high risk for psychosis will indeed be one of the 26% to progress to a clinically significant psychotic disorder. To examine the actual diagnostic accuracy, the authors then took gray matter volumes from the peak voxel, performed cross-validation analyses using a predictive linear model, and determined that the average predictive accuracy was only 62% (sensitivity = 61% and specificity = 65%). This means the single voxel measure incorrectly predicted that 39% of healthy UHR would become psychotic, while it missed a diagnosis in 35% who would later develop psychosis.



On the basis of these results would you recommend MRI scans of the left parahippocampal gyrus to refine the cohort given Seroquel to reduce or delay the risk of psychosis? I would say no, especially not if you're Australian (Dazzan et al., 2011). Another paper by many of the same authors reported that of 102 UHR Australians, 28 converted to a psychotic disorder, and these individuals showed volume reductions in frontal [and other] regions, relative to the UHR subgroup who remained healthy (Dazzan et al., 2011). Left parahippocampal gyrus was nowhere to be found. In fact, none of the 3 ROIs from Mechelli et al. were selected as ROIs by Dazzan et al. Furthermore, neither of these papers cited the other, despite the fact that they shared 8 authors in common.



In my view, the results thus far seem disappointing to those looking for the neuroanatomical correlates of psychiatric disorders. What does this mean for future structural MRI studies searching for changes that will predict the onset of psychosis?





References



Dazzan P, Soulsby B, Mechelli A, Wood SJ, Velakoulis D, Phillips LJ, Yung AR, Chitnis X, Lin A, Murray RM, McGorry PD, McGuire PK, Pantelis C. (2011). Volumetric Abnormalities Predating the Onset of Schizophrenia and Affective Psychoses: An MRI Study in Subjects at Ultrahigh Risk of Psychosis. Schizophr Bull. Apr 25. [Epub ahead of print]



McGorry PD, Purcell R, Goldstone S, Amminger GP. (2011). Age of onset and timing of treatment for mental and substance use disorders: implications for preventive intervention strategies and models of care. Curr Opin Psychiatry 24:301-6.



Mechelli, A., Riecher-Rossler, A., Meisenzahl, E., Tognin, S., Wood, S., Borgwardt, S., Koutsouleris, N., Yung, A., Stone, J., Phillips, L., McGorry, P., Valli, I., Velakoulis, D., Woolley, J., Pantelis, C., & McGuire, P. (2011). Neuroanatomical Abnormalities That Predate the Onset of Psychosis: A Multicenter Study. Archives of General Psychiatry, 68 (5), 489-495 DOI: 10.1001/archgenpsychiatry.2011.42

Polka-Dotted Brainbow

...because you know that polka dots are a Fall 2011 Fashion Trend!





No, it's not the Brainbow neuroimaging technique that uses fluorescent proteins to visualize individual neurons (Livet et al., 2007), it's Brains and Bows on Etsy, the e-commerce site that features handmade crafts. This fine polka-dotted brainbow (featuring an anatomically incorrect brain) is on sale for only $3.00:

This is a hand sewn high quality fabric bow! Approzx size: 3 inch x 2 1/2 inch. This bow comes in polk dot fabric that is hand sewn into bow with the cutest-creepiest little PINK brain ever! The bow has an a double prong alligator clip in back. These are limited edition and sure to sell out fast!!!

Other anatomically incorrect handmade crafts include this Crocheted Life Size Brain Plush:







You'll have to shell out $55 for this beauty, however.

This brain is the perfect snack, or a huggable anatomy plush toy, depending on your preference. Or perhaps you know a scarecrow, or a neurology major - but the main reason to get this is because it looks totally cool, especially when sitting non-chalantly on a shelf or coffee table.

Each brain is made to order and will take two weeks to complete, in addition to shipping. Your new brain will have a circumference of about 23 inches (measuring long ways), and about 18 inches around, making it a nice sized plush, or a small pillow.

I don't think this one will make it into the The Museum of Scientifically Accurate Fabric Brain Art....





And just in case the Etsy parody site regretsy wants to start a new category for WTF Brain items for sale (to join the infamous Vaginas), I nominate the truly horrifying Zombie Girl Eating a Bowl full of brains and guts. It's a Cigarette Id Case Business Card Holder Wallet, too!

This is an awesome D.I.Y. business card, ID, or cigarette case that is handmade by me and brand new-- you won't find this design anywhere but here because this is a SHS original!

[It's somehow comforting to know they're not mass produced in Japan...]

...although I do think SweetHeartSinner's Zombie Pinup Pillbox for Birth Control would make a fun gift for that special someone in your life!





Reference



Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW. (2007). Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450:56-62.

A New Sexual Femunculus?

Figure 3A (adapted from Komisaruk et al., 2011). Group-based composite view of the clitoral, vaginal, and cervical activation sites, all in the medial paracentral lobule, but regionally differentiated. We interpret this as due to the differential sensory innervation of these genital structures, i.e., clitoris: pudendal nerve, vagina: pelvic nerve,¹ and cervix: hypogastric and vagus nerves.


"Femunulus" is a neologism for "female homuculus"

The neuroanatomical definition of homunculus is a "distorted" representation of the sensorimotor body map (and its respective parts) overlaid upon primary somatosensory and primary motor cortices. The figure below illustrates the sensory homunculus, where each body part is placed onto the region of cortex that represents it, and the size of the body part is proportional to its cortical representation (and sensitivity). It's rare to see the genitals represented at all. And if they are present, they are inevitably male genitals.


Homunculus image from Reinhard Blutner.

See the G-Rated [i.e., genital-less] flash explanation of homunculus.


A New Clitoral Homunculus?

To remedy this puritanical and androcentric situation, Swiss scientists at University Hospital in Zurich conducted a highly stimulating study in 15 healthy women to map the somatosensory representation of the clitoris (Michels et al., 2009).

Michels and colleagues began by reviewing the work of Wilder Penfield et al.:

During the last 70 years the description of the sensory homunculus has been virtually a standard reference for various somatotopical studies (Penfield and Boldrey 1937; PDF). This map consists of a detailed description of the functional cortical representation of different body parts obtained via electrical stimulation during open brain surgery. In their findings they relied on reported sensations of different body parts after electrical stimulation of the cortex. Assessment of the exact location was generally difficult and sometimes led to conflicting results. The genital region was especially hard to assess due to difficulties with sense of shame.

In contrast to electrical stimulation of the brain, modern mapping studies have used sensory stimulation to map the penis with fMRI (e.g., Kell et al., 2005). But as of 2009, there were no comparable fMRI studies of female genitalia. So how is such a study conducted, methodologically speaking? Electrical stimulation of the dorsal clitoral nerve was compared to electrical stimulation of the hallux (big toe). It was all very clinical, no sexual arousal involved. Here's the experimental protocol (Michels et al., 2009):

Prior to the imaging session, two self-attaching surface disc electrodes (1 × 1 cm) were placed bilaterally next to the clitoris of the subjects so that we were able to stimulate the fibers of the dorsal clitoral nerve. Before the start of the experiment, electrical test stimulation was performed to ensure that subjects could feel the stimulation directly at the clitoris. In addition, the strength of electrical stimulation was adjusted to a subject-specific level, i.e. that stimulation was neither felt [as] painful nor elicited – in case of clitoris stimulation – any sexual arousal. Functional imaging was performed in a block design with alternating rest and stimulation conditions, starting with a rest condition. ... In addition to the clitoris stimulation, we performed in eight of the recorded subjects a second experimental session, in which we applied electrical stimulation of the right hallux using the same type of electrodes, stimulation and scan paradigm.

Their neuroimaging results revealed no evidence of clitoral representation on the medial wall (i.e., the paracentral lobule, as shown above in Komisaruk et al.'s Figure 3A and the male homunculus). Instead, electrical stimulation produced significant activations predominantly in bilateral prefrontal areas and the precentral, parietal and postcentral gyri, including S1 and S2. Click here to see Fig. 3 of Michels et al., 2009.

However, that experiment involved electrical stimulation of the dorsal clitoral nerve, which was not sexually arousing. What if the stimulation occurred in a more naturalistic fashion?


Even newer clitoral, vaginal, cervical and nipple homunculi?

Now, Komisaruk et al., (2011) have expanded the somatosensory map of female sexual organs by having the participants engage in self-stimulation of the clitoris, vagina, cervix, and nipple while laying in a 3T scanner. For comparison, the investigators stimulated the thumb and the big toe. Should we be concerned about differential movement artifact (of the head, hand, arm, pelvis) in these varied stimulation conditions? We'll leave that question aside for the moment and examine the experimental protocol, which consisted of 30 sec of rest and 30 sec of the various stimulation modalities, each followed by 30 sec rest (in 5 min blocks):

...Control trials consisted of an experimenter rhythmically tapping a participant's thumb or toe in separate trials to establish reference points on the sensory cortex. Experimental mapping trials consisted of participants self-stimulating, by hand or personal device, using “comfortable” intensity, the clitoris, anterior wall of the vagina, the cervix, or the nipple, in separate, randomized-sequence trials. Clitoral self-stimulation was applied using rhythmical tapping with the right hand. Vaginal self-stimulation (of the anterior wall) was applied using the participant's own stimulator (typically a 15 mm-diameter S-shaped acrylic rounded-top cylinder). Cervical self-stimulation was applied using a similar-diameter, glass or acrylic straight rounded-tip cylinder brought to the study by each participant. Nipple self-stimulation was applied using the right hand to tap the left nipple rhythmically...

What's a "comfortable" intensity, and how are we sure the hand and the dildo applied rhythmic tapping of the same frequency and intensity? Looking at Figure 2 below, you'll see that large swaths of lateral sensorimotor cortex were activated on the side contralateral to hand use (i.e., L side of the brain activated by R hand).² These activations seem to cover most of the sensory and motor homunculi, not just the arm, hand, and finger areas.

Figure 2 (adapted from Komisaruk et al., 2011). Three-axis (coronal, sagittal, and transaxial) views of the group-based responses to participant self-applied (clitoris, vagina, or cervix) stimulation ... The arrows indicate the sensory cortical regions activated by the various stimulated body regions. Clitoral, vaginal, and cervical self-stimulation activated the medial paracentral lobule. Note that the perineal (groin) region just lateral to the midline in the paracentral lobule was also activated... There was marked hand-related activation in the postcentral gyrus, and continuation of activation into the supplementary motor area immediately rostral to the sensory cortical responses... The secondary sensory cortex (SII; at the base of the homunculus) was activated under all the stimulus conditions...

To me, it looks like all the midline activations [including the toe activation, not shown here] bleed into motor areas including supplementary motor cortex, which is involved in both planning and inhibiting movement. We aren't given MNI coordinates to precisely locate the activations in 3D space, but my guess is that the clitoral, vaginal, and cervical regions are more overlapping than Figure 3A would lead you to believe. In fact, there is visible overlap between the vaginal and cervical regions, and the authors say this is due to unavoidable cross-stimulation in the cervical condition. Given the amount of motion artifact that likely occurred, a 4-5 mm difference in the foci of activation may not be entirely reliable in this particular study.³

The most surprising finding was that nipple stimulation largely overlapped with the genital regions:

Unexpectedly, nipple/breast self-stimulation activated not only the (expected) thoracic sensory homuncular region, but also the region of the paracentral lobule that overlaps with the region activated by clitoral, vaginal, or cervical self-stimulation. This finding is consistent with many women's reports that nipple/breast stimulation is erotogenic and can elicit orgasms...

The infamous Stuart Brody ["unprotected penile-vaginal sex is the only mature and worthwhile form of sex"] was an author on this paper, and of course he'll use these results as support for his prejudicial and boring view of sex. In my view, this study says nothing about different types of female orgasms and how they might be represented in the brain. There was no explicit mention of whether the women found the self-stimulation arousing at all, but the concluding sentence implies it was perceived as "just pressure." I'd recommend reading Dr Petra as an antidote to Brody.


Footnote

¹ I'm not sure there is one "pelvic nerve" per se in the human female, as opposed to in rats.

² You'll notice that Figure 3A better illustrates the bilateral nature of the activation, however [which could suggest mirror movement on the L side].

³ I'm not familiar enough with the human peripheral nervous system to say whether separate nerves innervate different female sexual regions with no overlap.

References

Kell CA, von Kriegstein K, Rösler A, Kleinschmidt A, Laufs H. (2005). The sensory cortical representation of the human penis: revisiting somatotopy in the male homunculus. J Neurosci. 25:5984-7.

Komisaruk, B., Wise, N., Frangos, E., Liu, W., Allen, K., & Brody, S. (2011). Women's Clitoris, Vagina, and Cervix Mapped on the Sensory Cortex: fMRI Evidence. The Journal of Sexual Medicine DOI: 10.1111/j.1743-6109.2011.02388.x

Michels, L., Mehnert, U., Boy, S., Schurch, B., & Kollias, S. (2009). The somatosensory representation of the human clitoris: An fMRI study NeuroImage.

Body mapping on the brain - revised homunculus from New Scientist.